Transgenic overexpression of glutathione S-transferase μ-type 1 reduces hypertension and oxidative stress in the stroke-prone spontaneously hypertensive rat

Olson, E., Pravenec, M., Landa, V., Koh-Tan, H. H. C., Dominiczak, A. F. , McBride, M. W. and Graham, D. (2019) Transgenic overexpression of glutathione S-transferase μ-type 1 reduces hypertension and oxidative stress in the stroke-prone spontaneously hypertensive rat. Journal of Hypertension, 37(5), pp. 985-996. (doi:10.1097/HJH.0000000000001960) (PMID:30308595)

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Abstract

Background: Combined congenic breeding and microarray gene expression profiling previously identified glutathione S-transferase m-type 1 (Gstm1) as a positional and functional candidate gene for blood pressure (BP) regulation in the stroke-prone spontaneously hypertensive (SHRSP) rat. Renal Gstm1 expression in SHRSP rats is significantly reduced when compared with normotensive Wistar Kyoto (WKY) rats. As Gstm1 plays an important role in the secondary defence against oxidative stress, significantly lower expression levels may be functionally relevant in the development of hypertension. The aim of this study was to investigate the role of Gstm1 in BP regulation and oxidative stress by transgenic overexpression of the Gstm1 gene. Method: Two independent Gstm1 transgenic SHRSP lines were generated by microinjecting SHRSP embryos with a linear construct controlled by the EF-1a promoter encoding WKY Gstm1 cDNA [SHRSP-Tg(Gstm1)1WKY and SHRSPTg(Gstm1)2WKY]. Results: Transgenic rats exhibit significantly reduced BP and pulse pressure when compared with SHRSP [systolic: SHRSP 205.2 3.7 mmHg vs. SHRSP-Tg(Gstm1)1WKY 175.5 1.6 mmHg and SHRSP-Tg(Gstm1)2WKY 172 3.2 mmHg, P< 0.001; pulse pressure: SHRSP 58.4 0.73 mmHg vs. SHRSP-Tg(Gstm1)1WKY 52.7 0.19 mmHg and SHRSP-Tg(Gstm1)2WKY 40.75 0.53 mmHg, P< 0.001]. Total renal and aortic Gstm1 expression in transgenic animals was significantly increased compared with SHRSP [renal relative quantification (RQ): SHRSP-Tg(Gstm1)1WKY 1.95 vs. SHRSP 1.0, P< 0.01; aorta RQ: SHRSP-Tg(Gstm1)1WKY 2.8 vs. SHRSP 1.0, P< 0.05]. Renal lipid peroxidation (malondialdehyde: protein) and oxidized : reduced glutathione ratio levels were significantly reduced in both transgenic lines when compared with SHRSP [malondialdehyde: SHRSP 0.04 0.009mmol/l vs. SHRSP-Tg(Gstm1)1WKY 0.024 0.002mmol/l and SHRSPTg(Gstm1)2WKY 0.021 0.002mmol/l; (oxidized : reduced glutathione ratio): SHRSP 5.19 2.26mmol/l vs. SHRSPTg(Gstm1)1WKY 0.17 0.111mmol/l and SHRSPTg(Gstm1)2WKY 0.471 0.223mmol/l]. Transgenic SHRSP rats containing the WKY Gstm1 gene demonstrate significantly lower BP, reduced oxidative stress and improved levels of renal Gstm1 expression. Conclusion: These data support the hypothesis that reduced renal Gstm1 plays a role in the development of hypertension.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McBride, Dr Martin and Dominiczak, Professor Anna and Koh-Tan, Dr Han Hui and Graham, Dr Delyth
Authors: Olson, E., Pravenec, M., Landa, V., Koh-Tan, H. H. C., Dominiczak, A. F., McBride, M. W., and Graham, D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Hypertension
Publisher:Lippincott Williams & Wilkins
ISSN:0263-6352
ISSN (Online):1473-5598
Published Online:10 October 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Journal of Hypertension 37(5):985-996
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
515251EuratransAnna DominiczakEuropean Commission (EC)241504RI CARDIOVASCULAR & MEDICAL SCIENCES
617771BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177RI CARDIOVASCULAR & MEDICAL SCIENCES
492451BHF 4 Year PhD ProgrammeAnna DominiczakBritish Heart Foundation (BHF)FS/09/052RI CARDIOVASCULAR & MEDICAL SCIENCES